| First Author | O'Brien KA | Year | 2012 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 32 |
| Issue | 9 | Pages | 2232-40 |
| PubMed ID | 22814751 | Mgi Jnum | J:201481 |
| Mgi Id | MGI:5514201 | Doi | 10.1161/ATVBAHA.112.254680 |
| Citation | O'Brien KA, et al. (2012) ADP-stimulated activation of Akt during integrin outside-in signaling promotes platelet spreading by inhibiting glycogen synthase kinase-3beta. Arterioscler Thromb Vasc Biol 32(9):2232-40 |
| abstractText | OBJECTIVE: Integrins mediate platelet adhesion and transmit outside-in signals leading to platelet spreading. Phosphoinositide 3-kinases (PI3Ks) play a critical role in outside-in signaling and platelet spreading; however, the mechanisms of PI3K activation and function in outside-in signaling are unclear. We sought to determine the role of the Akt family of serine/threonine kinases and activation mechanisms of the PI3K/Akt pathway in outside-in signaling. METHODS AND RESULTS: Akt inhibitors and Akt3 knockout inhibited platelet spreading on fibrinogen, indicating that Akt is important in integrin outside-in signaling. Akt inhibitors and Akt3 knockout also diminished integrin-dependent phosphorylation of glycogen synthase kinase-3beta. Inhibition of glycogen synthase kinase-3beta reversed the inhibitory effects of Akt3 knockout and inhibitors of Akt or PI3K on platelet spreading, indicating that glycogen synthase kinase-3beta is a downstream target of Akt in outside-in signaling. Integrin-dependent activation of the PI3K-Akt pathway requires Src family kinase. Akt phosphorylation is also significantly inhibited in ADP receptor P2Y12 knockout platelets and further inhibited in P2Y12 knockout platelets treated with a P2Y1 antagonist. Consistently, P2Y12 knockout and P2Y1 inhibition together reduced platelet spreading. CONCLUSIONS: These results demonstrate that integrin outside-in signaling and platelet spreading requires Src family kinase-dependent and ADP receptor-amplified activation of the PI3K-Akt-GSK-3beta pathway. |
